1. Field of the Invention
This invention is concerned with certain novel phenoxyalkylcarboxylic acid derivatives which have strong and selective leukotriene antagonist activity, and are useful for prevention and treatment of allergic diseases such as bronchial asthma and so on, their intermediates and their preparation processes thereof.
Moreover, it relates to certain novel phenoxyalkylcarboxylic acid derivatives of the general formula (I), wherein R1 indicates hydrogen atom, methyl group or ethyl group, m is an integer from 2 to 5, and n is an integer from 3 to 8, X1 and X2 each independently represents sulfur atom, oxygen atom, sulfinyl group or sulfonyl group, proviso X1 and X2 are not simultaneously oxygen atom; their alkali salts and hydrates thereof.
2. Description of the Prior Art
Leukotrienes (leukotriene C4, D4, E4), which are metabolites of arachidonic acid through 5′-lipoxygenase pathway, are constituents of SRS-A (slow reacting substance of anaphylaxis), being an important mediator of the immediate type allergic diseases such as bronchial asthma. Accordingly, the drugs which exert antagonistic effects on leukotrienes are promising in the treatment of allergic diseases. But, only few drugs having those effects through the internal use are known and none is practically used.
Compounds having somewhat similar structure with those of the present invention are described in Japanese Patent Unexamined Publication (Kokai) Sho No. 58-189137 which corresponds to U.S. Pat. No. 4,507,498. These compounds can be characterized by the ether bond, but they never have thioether bond and thus, they are structurally different from the compounds of the present invention. Moreover, the compounds described in the art have been revealed to be less effective and are not useful as compared with the compounds of the present invention.
3. Detailed Description of the Invention
As the result of diligent studies about leukotriene antagonists, the inventors have found that the compounds represented by the general formula (I) possess strong and selective leukotriene antagonist activity even afier an oral administration and further found that they have surprisingly therapeutic effects on airway hyperreactivity induced in guinea pigs, which lead to completion of the present invention.
According to the present invention, the compounds of the general formula (I) can be prepared on the hereinafter mentioned routes. (1) Compound of the general formula (Ia) can be prepared by allowing compounds of the general formula (II) to react with compounds of the general formula (III) (wherein R2 indicates methyl group or ethyl group, m is an integer from 2 to 5, n is an integer from 3 to 8, X1 indicates sulfur atom, oxygen atom, sulfinyl group or sulfonyl group, X3 indicates sulfur atom or oxygen atom, proviso X1 and X3 are not simultaneously oxygen atom) (wherein R2, n and X3 are as defined in the above) (wherein Y indicates, halogen atom and X1 are as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature. In addition, the presence of an inorganic base, for example potassium carbonate or sodium carbonate etc. and further the addition of potassium iodide are also recommendable.
(2) Compounds represented by the general formula (Ib) can be prepared by allowing compounds of the general formula (IV) to react with compounds of formula (V). (wherein R2 indicates methyl group or ethyl group, m is an integer from 2 to 5, n is an integer from 3 to 8, X2 indicates sulfur atom, oxygen atom, sulfinyl group or sulfonyl group and X3 indicates sulfur atom or oxygen atom, proviso X2 and X3 are not simultaneously oxygen atom) (wherein Y1 indicates halogen atom, and R2, X2, m and n are as defined in the above) (wherein X3 is as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature. In addition, the presence of an inorganic base, for example potassium carbonate or sodium carbonate etc. and further the addition of potassium iodide are also recommendable.
(3) Compounds represented by the general formula (IIa) can be prepared by allowing compounds of the general formula (VI) to react with compounds of the general formula (VII), followed by removing the protective group. (wherein R2 indicates methyl group or ethyl group and n is an integer from 3 to 8) (wherein R3 indicates a protective group)Y2−(CH2)nCOOR2   (VII) (wherein Y2 indicates halogen atom, and R2 and n are as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature. In addition, the presence of an inorganic base, for example potassium carbonate or sodium carbonate and further the addition of potassium iodide are also recommendable.
In the compounds of the general formula (VI), dimethylaminocarbonyl group or benzyl group etc. can be exemplified as the protective group for thiol group.
(4) The compounds represented by the general formula (IIa) can also be prepared by the following process. The compounds of the general formula (VI) are allowed to react with compounds of the general formula (VIIIa) to give compounds of the general formula (IX).Y—(CH2)n—Y1   (VIIIa) (wherein Y and Y1 indicate identical or different halogen atom, and n is an integer from 3 to 8) (wherein R3 indicates a protective group, Y1 and n are as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide under a reaction temperature of the room temperature to the solvent refluxing temperature. Then, the compounds represented by the general formula (IX) are allowed to react with sodium cyanide or potassium cyanide to give compounds of the general formula (X). (wherein R3 and n are as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example dimethyl sulfoxide or dimethylformamide under a temperature of the room temperature to 100° C. Further, the compounds represented by the general formula (X) are subjected to hydrolysis and then to esterification with alcohol to give the compounds of the general formula (IIa). The hydrolysis of nitrile proceeds preferably with sodium hydroxide or potassium hydroxide in aqueous solution, and the esterification is preferably performed by refluxing in alcohol and in the presence of conc. sulfuric acid or a certain amount of a catalyst.
(5) Compounds represented by the general formula (IVa) can be prepared by allowing the compounds of the general formula (IIa) to react with compounds of the general formula (VIII). (wherein R2 indicates methyl group or ethyl group, Y1 indicates a halogen atom, m is an integer from 2 to 5 and n is an integer from 3 to 8)Y—(CH2)m—Y1   (VIII) (wherein Y indicates a halogen atom, Y1 and m are as defined in the above)
It is preferable that this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide under a reaction temperature of the room temperature to the solvent refluxing temperature. In addition, the presence of an inorganic base, for example potassium carbonate or sodium carbonate and further the addition of potassium iodide are also preferable.
(6) Compounds of the general formula (III) or (IV), in which X1 and X2 are both sulfinyl group, can be prepared by oxidizing compounds represented by the general formula (IIIa) or (IVa). (wherein Y indicates a halogen atom and m is an integer from 2 to 5) (wherein Y1 indicates a halogen atom, R2 indicates methyl group or ethyl group, m is an integer from 2 to 5 and n is an integer from 3 to 8)
The compounds of the general formula (III) or (IV) can typically be prepared by allowing the compounds represented by the general formula (IIIa) or (IVa) to react with a mild oxidizing agent, for example m-chloroperbenzoic acid, hydrogen peroxide etc., of equimolar or excess amount in an adequate solvent, for example methylene chloride, alcohol etc. respectively.
(7) Compounds of the general formula (III) or (IV), in which X1 and X2 are both sulfonyl group, can be prepared by allowing the compounds of the general formula (IIIa), (IVa) to react likewise as in (6), but with not less than bimolar amount of the mild oxidizing agent.
(8) Compounds of the general formula (I), in which R1 is methyl group or ethyl group X1 is oxygen atom or sulfonyl group and X2 is sulfinyl group, and compounds of the general formula (I), in which R1 is methyl group or ethyl group, X1 is sulfinyl group and X2 is an oxygen atom or sulfonyl group, can be respectively prepared by allowing the compounds represented by the general formula (Ia′), (Ib′) to react with equimolar or excess amount of the mild oxidizing agent likewise as in (6). (wherein R2 indicates methyl group or ethyl group, m is an integer from 2 to 5, n is an integer from 3 to 8, and X1 indicates oxygen atom or sulfonyl group) (wherein R2, m, n and X2 are defined in the above)
(9) Compounds of the general formula (I), in which R1 is methyl group or ethyl group, X1 oxygen atom or sulfonyl group and X2 is sulfonyl group, and compounds of the general formula (I), in which R1 is methyl group or ethyl group, X1 is sulfonyl group and X2 is oxygen atom or sulfonyl group can be respectively prepared by allowing the compounds represented by the general formula (Ia′), (Ib′) to react with the mild oxidizing agent likewise as in (6) but with not less than bimolar amount.